We have conducted several pre-clinical HIV/SIV vaccine studies in non-human primates in which systemic and mucosal antibody responses have been elicited. The antibodies have exhibited multiple functions, including neutralization, activities that bridge innate and adaptive immune responses, and inhibition of HIV transmission across mucosal surfaces. Some of these non-neutralizing antibody activities depend on non-immune effector cells to kill virus-infected cells. The vaccine-induced antibodies provide specificity for the killing of HIV or SIV-infected cells by recongizing and targeting the viral-infected cells. We have shown that inclusion of a boost with an HIV envelope protein, following initial immunization with a replication-competent adenovirus recombinant expressing the HIV envelope, elicits HIV specific antibodies and contributes to vaccine-elicited protection. Several of the antibody activities induced by vaccination are correlated with protection against HIV or SIV, reflected by lower levels of viremia in blood and tissues. These studies have illustrated the value of the envelope protein in HIV vaccine design, and the value of multiple antibody activities in vaccine-elicited proteciton.